The corpus callosum, formed between the 8th and 14th weeks of fetal development, is the principal fiber tract that connects the two cerebral hemispheres. Agenesis of the corpus callosum (ACC) has an estimated incidence of 1:4,000 live births. Patients with ACC can have significant developmental disability and seizures and may have cognitive and behavioral impairment such as autism, obsessive compulsive disorder or attention deficit hyperactivity disorder. Callosal anomalies have also been found consistently in drug-naive schizophrenic patients, suggesting that understanding the causes of ACC may have broad implications for understanding other neurobehavioral disorders. The genetic causes for ACC are largely unknown, however, certain cytogenetic loci are repeatedly deleted in ACC patients, suggesting that ACC genes reside in these loci and that missing one copy of the gene can cause ACC. Epidemiological data suggest that 2% of affected individuals have first-degree relatives with ACC, consistent with the possibility that many ACC patients may have de novo causative mutations. This role for gene dosage in ACC is also evident in animal models;deletion of genes involved in callosal formation frequently results in multiple pathfinding defects in the CMS, whereas heterozygous deletion may only result in callosal anomalies. We have undertaken a comprehensive approach to study the clinical, radiographic and genetic features of at least 200 ACC patients and their families. We have begun to test our cohort for chromosomal copy number changes using genomic microarrays. In the first 25 patients, we identified three submicroscopic de novo deletions that correlate with ACC, suggesting that de novo deletions may occur in up to 20% of ACC patients. We hypothesize that some of the remaining 80% will have inactivating point mutations in ACC causative genes contained within one of these intervals. In light of these findings and hypotheses, for this grant we propose to tackle the following Aims: 1. To continue to develop a comprehensive database of clinical, historical and radiologic information on an initial 200 patients with callosal agenesis/dysgenesis. 2. To narrow down previously identified ACC chromosomal intervals and to identify novel ACC intervals utilizing the UCSF 32,000 BAG microarray on 200 ACC patients. 3. To identify inactivating mutations in candidate ACC genes, which are contained in three ACC-associated chromosomal intervals: 2q37.1, 6q27 and 3q13.1.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Scientist Development Award - Research (K02)
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NST-2 Subcommittee (NST)
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Riddle, Robert D
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Lau, Yolanda C; Hinkley, Leighton B N; Bukshpun, Polina et al. (2013) Autism traits in individuals with agenesis of the corpus callosum. J Autism Dev Disord 43:1106-18
Jones-Davis, Dorothy M; Yang, Mu; Rider, Eric et al. (2013) Quantitative trait loci for interhemispheric commissure development and social behaviors in the BTBR T? tf/J mouse model of autism. PLoS One 8:e61829
Hinkley, Leighton B N; Marco, Elysa J; Findlay, Anne M et al. (2012) The role of corpus callosum development in functional connectivity and cognitive processing. PLoS One 7:e39804
Marco, Elysa J; Harrell, Kathryn M; Brown, Warren S et al. (2012) Processing speed delays contribute to executive function deficits in individuals with agenesis of the corpus callosum. J Int Neuropsychol Soc 18:521-9
Cabrera, Michelle T; Winn, Bryan J; Porco, Travis et al. (2011) Laterality of brain and ocular lesions in Aicardi syndrome. Pediatr Neurol 45:149-54
Osbun, Nathan; Li, Jiang; O'Driscoll, Mary C et al. (2011) Genetic and functional analyses identify DISC1 as a novel callosal agenesis candidate gene. Am J Med Genet A 155A:1865-76
O'Driscoll, Mary C; Black, Graeme C M; Clayton-Smith, Jill et al. (2010) Identification of genomic loci contributing to agenesis of the corpus callosum. Am J Med Genet A 152A:2145-59
Wahl, Michael; Strominger, Zoe A; Wakahiro, Mari et al. (2010) Diffusion tensor imaging of Aicardi syndrome. Pediatr Neurol 43:87-91
Glass, Hannah C; Shaw, Gary M; Ma, Chen et al. (2008) Agenesis of the corpus callosum in California 1983-2003: a population-based study. Am J Med Genet A 146A:2495-500